Oxidative stress is involved in the onset of several age-related neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD). The principal source of oxidative stress in cells is aerobic respiration in the mitochondria, which inevitably results in the production of superoxide anions, hydrogen peroxide and hydroxyl radicals. Although the primary enzymatic mechanisms (superoxide dismutase, glutathione peroxidase, and catalase) by which cells deal with these reactive oxygen species are well-known, much less is known about the myriad of other factors that determine the net sensitivity of particular cells to oxidative damage. This differential sensitivity is particularly noticeable and important in the brain where distinct populations of cells are preferentially damaged in the different neurodegenerative disorders. To combat these disorders, it is important to know as much as possible about all the ways that neuronal cells can resist oxidative stress. Toward this end, this project will investigate genetic changes that can confer resistance to oxidative stress-induced cytotoxicity in neuronal cells in culture. This research will contribute to an understanding of the network of molecular mechanisms that modulate the survival of neuronal cells in response to reactive oxygen species, and help point the way toward therapeutic interventions that promote neuronal survival in vivo.